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Infection and Immunity, May 2007, p. 2136-2142, Vol. 75, No. 5
0019-9567/07/$08.00+0     doi:10.1128/IAI.01589-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Leishmania donovani-Induced Ceramide as the Key Mediator of Akt Dephosphorylation in Murine Macrophages: Role of Protein Kinase C{zeta} and Phosphatase{triangledown}

Ranadhir Dey,1 Nivedita Majumder,1 Surajit Bhattacharjee,1 Suchandra Bhattacharyya Majumdar,1 Rajdeep Banerjee,2 Sandipan Ganguly,2 Pradeep Das,2 and Subrata Majumdar1*

Department of Microbiology, Bose Institute, Kolkata, India,1 National Institute of Cholera and Enteric Diseases, Beliaghata, Kolkata, India2

Received 2 October 2006/ Accepted 22 December 2006

Leishmania donovani is an intracellular protozoan parasite that impairs the host macrophage immune response to render it suitable for its survival and establishment. L. donovani-induced immunosuppression and alteration of host cell signaling is mediated by ceramide, a pleiotropic second messenger playing an important role in regulation of several kinases, including mitogen-activated protein kinase and phosphatases. We observed that the endogenous ceramide generated during leishmanial infection led to the dephosphorylation of protein kinase B (PKB) (Akt) in infected cells. The study of ceramide-mediated Akt phosphorylation revealed that Akt was dephosphorylated at both Thr308 and Ser473 sites in infected cells. Further investigation demonstrated that ceramide was also responsible for the induction of PKC{zeta}, an atypical Ca-independent stress kinase, as well as the ceramide-activated protein phosphatases (e.g., protein phosphatase 2A [PP2A]). We found that Akt dephosphorylation was mediated by ceramide-induced PKC{zeta}-Akt association and PP2A activation. In addition, treatment of L. donovani-infected macrophages with PKC{zeta}-specific inhibitor peptide could restore the translocation of phosphorylated Akt to the cell membrane. This study also revealed that ceramide is involved in the inhibition of proinflammatory cytokine tumor necrosis factor alpha release by infected macrophages. These observations strongly suggest the importance of ceramide in the alteration of normal cellular functions, impairment of the kinase/phosphatase balance, and thereby establishment of leishmaniasis in the hostile macrophage environment.

* Corresponding author. Mailing address: Dept. of Microbiology, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata, India. Phone: (91) (33) 2337-9416. Fax: (91) (33) 2334-3886. E-mail: subrata{at}bic.boseinst.ernet.in

{triangledown} Published ahead of print on 12 January 2007.

Editor: W. A. Petri, Jr.

Infection and Immunity, May 2007, p. 2136-2142, Vol. 75, No. 5
0019-9567/07/$08.00+0     doi:10.1128/IAI.01589-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





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